Different Effects of Valproic Acid on SLC12A2, SLC12A5 and SLC5A8 Gene Expression in Pediatric Glioblastoma Cells as an Approach to Personalised Therapy

Abstract

Valproic acid (VPA) is a histone deacetylase inhibitor with sex-specific immunomodulatory and anticancer effects. This study aimed to investigate the effect of 0.5 and 0.75 mM VPA on NKCC1 (SLC12A2), KCC2 (SLC12A5) and SLC5A8 (SLC5A8) co-transporter gene expressions in pediatric PBT24 (boy’s) and SF8628 (girl’s) glioblastoma cells. The SLC12A2, SLC12A5 and SLC5A8 RNA expressions were determined by the RT-PCR method. The SLC12A2 and SLC5A8 expressions did not differ between the PBT24 and SF8628 controls. The SLC12A5 expression in the PBT24 control was significantly higher than in the SF8628 control. VPA treatment significantly increased the expression of SLC12A2 in PBT24 but did not affect SF8628 cells. VPA increased the SLC12A5 expression in PBT24 and SF8628 cells. The SLC12A5 expression of the PBT24-treated cells was significantly higher than in corresponding SF8628 groups. Both VPA doses increased the SLC5A8 expression in PBT24 and SF8628 cells, but the expression was significantly higher in the PBT24-treated, compared to the respective SF8628 groups. The SLC5A8 expression in PBT24-treated cells was 10-fold higher than in SF8628 cells. The distinct effects of VPA on the expression of SLC12A2, SLC12A5 and SLC5A8 in PBT24 and SF8628 glioblastoma cells suggest differences in tumor cell biology that may be gender-related.

Preclinical Study in Mouse Thymus and Thymocytes: Effects of Treatment with a Combination of Sodium Dichloroacetate and Sodium Valproate on Infectious Inflammation Pathways

“…Slc5a8 expression can be upregulated by DNA demethylation. VPA can induce the effect on Slc5c8 gene expression upregulation via DNA demethylation in cancer cells [ 81 , 84 ].…”

The Comparative Experimental Study of Sodium and Magnesium Dichloroacetate Effects on Pediatric PBT24 and SF8628 Cell Glioblastoma Tumors Using a Chicken Embryo Chorioallantoic Membrane Model and on Cells In Vitro

“…Recently the different temozolomide and valproic acid effects on tumorigenesis mechanisms have been reported, such as their effect on tumor growth, the histological expression of PCNA and EZH2 in tumor cells, Na-K-2Cl, K-Cl, and SLC5A8 co-transporter gene expression in pediatric glioblastoma PBT24 and SF8628 cell tumors on chick embryo chorioallantoic membranes (CAM) and on corresponding cells in vitro, highlighting the importance of studies on efficacy in the context of individualized anticancer therapy [ 37 , 38 ]. This study’s novelty lies in the differential effect of the active substance DCA‘s anions on PBT24 and SF8628 tumors on the CAM and the cells in vitro, comparing the differences in the impact of the studied NaDCA and MgDCA salts.…”

Differential Impact of Valproic Acid on SLC5A8, SLC12A2, SLC12A5, CDH1, and CDH2 Expression in Adult Glioblastoma Cells

“…Treatment with a combination of VPA and dichloroacetate significantly increased Slc5a8 gene expression and showed a significant anti-inflammatory effect on thymocytes from male mice [19], and treatment of T lymphocytes from males and females with this combination showed a significant anti-inflammatory effect and gender-related differences [20]. It was reported that different VPA effect the expression of the SLC12A2 (NKCC1) and SLC12A5 (KCC2) co-transporter genes in pediatric glioblastoma PBT24 (boys) and SF8628 (girls) cells [21]. The molecular and clinical role of cation-chloride co-transporters illustrates the significant association of KCC2 and NKCC1 with tumorigenesis.…”

“…VPA-treated GBM cells secreted high amphiregulin levels, whose expression was positively correlated with resistance to TMZ of different GBM cells [23]. VPA induces the activation of the Na + -K + -2Cl -co-transporter (NKCC1), significantly increasing the expression of the NKCC1 gene (SLC12A2) in PBT24 but not affecting SF8628 cells [21]. The TMZ caused significantly increased RNA expression of the SLC12A2 in both PBT24 and SF8628 cell types [24].…”